Activation of the tissue factor (TF) pathway of blood coagulation is associated with increased blood thrombogenicity and increases in markers of blood coagulation levels may in part explain the high degree of poor neurological outcome and recurrence of stroke in patients with acute ischemic stroke (AIS). We have shown that membrane-bound tissue factor procoagulant activity (TF-PCA) and plasma activated factor VII (FVIIa) and markers of thrombin generation, prothrombin fragment 1.2 (F1.2) and thrombin- antithrombin complexes (TAT), are markedly elevated after AIS. While these markers are highest in patients with T2DM and hyperglycemia, the effect of blood glucose (BG) control on levels of blood coagulation markers and their relationship with stroke outcome is unknown. Therefore, a better understanding of the relationhips between these and other markers of blood coagulation and clinical outcomes after stroke and how hyperglycemia control modulates these markers holds great promise for management of acute ischemic stroke. The Insights on Selected Procoagulation Markers and Outcomes in Stroke Trial (I-SPOT): Response to Insulin Administration and Blood Glucose Control proposal is designed to accompany the Stroke Hyperglycemia Insulin Network Effort (SHINE) clinical trial, a Phase III multicenter, randomized, controlled trial planning to determine the efficacy an validate the safety of glycemic control in stroke patients. The SHINE trial will recruit 1,400 AIS patients with Type II diabetes mellitus (T2DM) and hyperglycemia, each receiving 3 days of hyperglycemia control with intravenous (IV) insulin therapy or control therapy with subcutaneous (SQ) insulin. Blood coagulation marker levels [whole blood TF-PCA~ plasma coagulation factors VII, VIIa, and VIII~ plasma TAT~ D-dimer~ tissue factor pathway inhibitor (TFPI)~ and plasminogen activator inhibitor-1 (PAI-1)] will be measured before and at 48 hours after the start of treatment. Baseline and temporal changes in biomarkers levels will be compared between treatment groups.
The aims and hypotheses of the I-SPOT study are to 1) Compare the effects of strict hyperglycemia control with standard treatment of hyperglycemia on membrane- bound TF-PCA and markers of blood coagulation in T2DM patients after AIS and 2) Determine the relationship between circulating TF-PCA and markers of blood coagulation and functional neurological outcome in SHINE treatment and control patients. We anticipate that 1) the decrease in levels of markers of blood coagulation will be greater in patients treated with IV insulin to reduce BG than in patients treated with SQ Insulin as the standard fashion and 2) the decrease in levels of markers of blood coagulation will be greater in patients with than without favorable outcome (defined as the baseline stroke severity adjusted measure of functional ability at 90 days after acute stroke). Moreover, we expect that hyperglycemia control will modulate the relationship between blood coagulation levels and functional outcome in T2DM patients providing further insights on the effects of glucose regulation on the TF pathway of blood coagulation in acute stroke.

Public Health Relevance

Over 750,000 people have strokes in the US annually. Approximately 40% percent of patients with acute ischemic stroke (AIS) are hyperglycemic at presentation. Patients with AIS, especially those with hyperglycemia, are at risk for both poor neurological outcome and recurrence of stroke. Determining the factors associated with these negative outcomes and discovering ways to modulate them is critical for treatment of AIS patients. We have previously demonstrated that markers of activation of the tissue factor (TF) pathway of blood coagulation are elevated in AIS patients, particularly those with type II diabetes mellitus (T2DM).1 Recognizing that AIS outcomes are worse in patients with hyperglycemia and T2DM2, we hypothesize that the negative outcomes may be due to the effect of DM and/or hyperglycemia on the TF pathway. We propose to study the effect of glucose levels and glucose regulation on the TF pathway in AIS patients and seek to define the relationship between glucose levels, markers of activation of TF pathway, and clinical outcome. The results of this study will have enormous impact on the stroke community as healthcare providers currently manage hyperglycemic acute stroke patients every day without adequate evidence of best therapy. Regardless of the results of this study, it will provide an understanding of the potential mechanisms of action of stroke therapy and guide acute stroke management across the US.